Glaucoma is a multifactorial, neurodegenerative disease and the second most important cause of irreversible blindness (Quigley, 1996, Br J Ophthalmol 80, 389-393). This disease is characterized by progressive retinal ganglion cell apoptosis, resulting in visual field loss. Current treatment of this disease is directed towards the reduction of intraocular pressure (IOP), which is the main risk factor for glaucoma (Collaborative Normal-Tension Glaucoma Study Group, 1998, Am J Opthalmol 126, 487-497).
Of all currently used treatments to lower IOP, glaucoma filtration surgery (trabeculectomy), or shortly filtration surgery, was shown to be the most effective (Burr et al., 2005, Cochrane Database Syst Rev 18(2):CD004399; Hitchings, 1998, Arch Ophthalmol 116, 241-242). A trabeculectomy creates a “controlled” leak of fluid (aqueous humor) from the eye, which percolates under the conjunctiva. During the operation a piece of trabecular meshwork in the drainage angle of the eye is removed, creating an opening. The opening is partially covered with a flap of tissue from the sclera and conjunctiva. A small conjunctival “bleb” (bubble) appears at the junction of the cornea and the sclera (limbus) where this surgically produced valve is made.
In 30% of the cases, however, the constructed channel closes due to excessive scar tissue formation, resulting in surgical failure (Addicks et al., 1983, Arch Ophthalmol 101, 795-798). The 4 important processes contributing to post-operative conjunctival scarring are: clot formation, inflammation, angiogenesis and fibrosis (Lee et al., 1995, J Ocul Pharmacol Ther 11, 227-232; Lama & Fechtner, 2003, Surv Ophthalmol 48, 314-346). Indeed, increased conjunctival infiltration of inflammatory cells and Tenon fibroblasts (Hitchings & Grierson, 1983, Trans Ophthalmol Soc UK 103, 84-88; Skuta & Parrish, 1987, Surv Ophthalmol 32, 149-170), and higher levels of bleb vascularisation (Jampel et al., 1988, Arch Ophthalmol 106, 89-94) are associated with surgical failure. These processes are mediated by various cytokines (e.g. IL-1 and INF-α2b) and growth factors (e.g. PDGF, FGF, TGF-β1 and VEGF (Lama & Fechtner, 2003; Gillies & Su, 1991, Aust NZ J Ophthalmol 19, 299-304)). Peroperative anti-mitotics, such as mitomycin-C and 5-Fluorouracyl can improve surgical outcome (Quigley, 1996; Katz et al., 1995, Ophthalmol 102, 1263-1269). However, these antimetabolites carry a risk of vision-threatening complications such as scleral thinning and infections (Lama & Fechtner, 2003; Hitchings & Grierson, 1983; Skuta & Parrish, 1987; Jampel et al., 1988; Gillies & Su, 1991; Katz et al., 1995; Greenfield et al., 1998, Arch Ophthalmol 116, 443-447). Furthermore, blocking TGF-β seemed promising in animal models (Cordeiro et al., 2003, Gene Ther 10, 59-71), but was not efficient in a clinical study (CAT-152 0102 Trabeculectomy Study Group, Kwah, Grehn, 2007, Ophthalmol 114, 1822-1830). The number of post-trabeculectomy interventions expressed as the incidence of post-surgery “bleb manipulations” was reported to be as high as 78% (King et al., 2007, Br J Ophthalmol 91, 873-877). Therefore, there is still a need for alternative strategies to prevent filtration failure and, thus, to reduce the incidence of bleb manipulations.
Microplasmin is a recombinant protein that dissolves blood clots by degrading fibrin. Recently, microplasmin has been shown to be efficient, well tolerated and safe for intra-ocular use (WO 2004/052228) and was approved by FDA in October 2012 for treating vitreomacular adhesion (JETREA®; non-proprietary name: ocriplasmin). Results of the phase III clinical trials leading to this approval were published by Stalmans et al. (2012, N Engl J Med 367, 606-615). Plasmin was previously shown to be able to induce PVD as well (e.g. U.S. Pat. No. 5,304,118). The mechanism by which PVD is induced by plasmin or microplasmin is currently not fully understood. Unsupported by any or any conclusive experimental data, WO 2009/073457 and WO 2009/067407 propose subconjunctival plasmin injection for rescuing filtering blebs and the use of matrix metalloproteinase activating proteases for reducing IOP, respectively. WO 2011/023805 provides the evidence that anterior chamber injection of microplasmin was effective in prolonging bleb survival, i.e., the mode of administration of microplasmin in this indication is determining success.
Pegaptanib is a pegylated anti-VEGF aptamer (VEGF=vascular endothelial growth factor), a single strand of nucleic acid (50 kDa). It specifically binds the VEGF165 isoform, thereby preventing the binding to the heparin binding domain. Van Bergen et al. 2011 (Exp Eye Res 93, 689-699) showed that single or repeated injection of pegaptanib after glaucoma filtration surgery (in a rabbit model) had marginal effect on bleb area and bleb survival. Bevacizumab is an antibody inhibiting all forms of VEGF-A. Li et al. 2009 (Invest Ophthalmol Vis Sci 50, 5217-5225) disclosed the effect of bevacizumab on glaucoma filtration surgery (in a rabbit model) which was, judging from the reported effect on bleb area, limited.